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ACUTE LYMPHOBLASTIC LEUKEMIA

Development of osteonecrosis and improved survival in B-ALL: results of Children’s Oncology Group Trial AALL0232

Leukemia volume 38, pages 258–265 (2024)Cite this article

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Abstract

Osteonecrosis is a significant toxicity of acute lymphoblastic leukemia (ALL) therapy. In retrospective analyses, superior event-free survival was noted among affected adolescents in an earlier trial. We prospectively assessed osteonecrosis incidence, characteristics, and risk factors in patients 1–30 years with newly diagnosed high-risk B-ALL on COG AALL0232. Patients were randomized to induction dexamethasone vs prednisone, and interim maintenance high-dose methotrexate vs escalating-dose Capizzi methotrexate/pegaspargase. Event-free and overall survival were compared between patients with/without imaging-confirmed osteonecrosis. Osteonecrosis developed in 322/2730 eligible, evaluable patients. The 5-year cumulative incidence was 12.2%. Risk was greater in patients ≥10 years (hazard ratio [HR], 7.23; P < 0.0001), particularly females (HR, 1.37; P = 0.0057), but lower in those with asparaginase allergy (HR, 0.60; P = 0.0077). Among rapid early responders ≥10 years, risk was greater with dexamethasone (HR, 1.84; P = 0.0003) and with prednisone/Capizzi (HR, 1.45; P = 0.044), even though neither therapy was independently associated with improved survival. Patients with osteonecrosis had higher 5-year event-free (HR, 0.51; P < 0.0001) and overall survival (HR, 0.42; P < 0.0001), and this was directly attributable to reduced relapse rates (HR, 0.57; P = 0.0014). Osteonecrosis in high-risk B-ALL patients is associated with improved survival, suggesting an important role for host factors in mediating both toxicity and enhanced efficacy of specific therapies.

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Fig. 1: CONSORT diagram.
Fig. 2: Cumulative incidence of osteonecrosis by treatment.
Fig. 3: Event-free and overall survival by osteonecrosis status.
Fig. 4: Cumulative incidence of relapse by osteonecrosis status.

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Data availability

The COG Data Sharing policy describes the release and use of COG individual subject data for use in research projects in accordance with National Clinical Trials Network (NCTN) Program and NCI Community Oncology Research Program (NCORP) Guidelines. Only data expressly released from the oversight of the relevant COG Data and Safety Monitoring Committee (DSMC) are available to be shared. Data are available to researchers who wish to analyze the data in secondary studies to enhance the public health benefit of the original work and agree to the terms and conditions of use. Requests for access to COG protocol research data should be sent to: datarequest@childrensoncologygroup.org. Data are available to researchers whose proposed analysis is found by COG to be feasible and of scientific merit and who agree to the terms and conditions of use. For all requests, no other study documents, including the protocol, will be made available and no end date exists for requests.

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Acknowledgements

This work was supported by COG Chair’s Operations grants U10 CA98543 and U10 CA180886, COG Statistics and Data Center grants U10 CA098413 and U10 CA180899, and St. Baldrick’s Foundation funding. The study is registered at ClinicalTrials.gov, number NCT00075725. MLL is an Endowed Professor of Pediatric Cancer Research, The Aldarra Foundation Endowed Chair, Bill and June Boeing, Founders. EAR is the Kids of NYU Foundation Professor at NYU Langone Health. SPH is the Jeffrey E. Perelman Distinguished Chair in Pediatrics at The Children’s Hospital of Philadelphia. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. HARP Pharma Consulting, Mystic, CT, USA

    Leonard A. Mattano Jr

  2. Department of Global Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Meenakshi Devidas

  3. Division of Pediatric Hematology, Oncology, Bone Marrow Transplantation, and Cellular Therapy, Seattle Children’s Hospital, Seattle, WA, USA

    Mignon L. Loh

  4. The Ben Towne Center for Childhood Cancer Research, University of Washington, Seattle, WA, USA

    Mignon L. Loh

  5. Department of Pediatrics, New York University Langone Medical Center, New York, NY, USA

    Elizabeth A. Raetz & William L. Carroll

  6. Perlmutter Cancer Center at New York University Langone Health, New York, NY, USA

    Elizabeth A. Raetz & William L. Carroll

  7. Department of Biostatistics, University of Florida, Gainesville, FL, USA

    Zhiguo Chen

  8. University of Texas Southwestern Medical Center, Dallas, TX, USA

    Naomi J. Winick

  9. Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Stephen P. Hunger

  10. The Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Stephen P. Hunger

  11. Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA

    Stephen P. Hunger

  12. Maine Children’s Cancer Program, Scarborough, ME, USA

    Eric C. Larsen

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Contributions

All authors participated in protocol development and data collection. LAM, MD, MLL, YD, ZC, and SPH analyzed the data and wrote the draft manuscript. All authors reviewed the paper, provided input on content and interpretation of results, and approved the final version. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Leonard A. Mattano Jr.

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LAM has received consulting fees from Novartis and Pfizer, and owns stock in Pfizer. MLL has received consulting fees from Medsix Therapeutics. SPH owns stock in Amgen, and has received honoraria from Amgen and Servier, and consulting fees from Novartis. The other authors declare no competing financial interests.

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Mattano, L.A., Devidas, M., Loh, M.L. et al. Development of osteonecrosis and improved survival in B-ALL: results of Children’s Oncology Group Trial AALL0232. Leukemia 38, 258–265 (2024). https://doi.org/10.1038/s41375-023-02099-1

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